Disubstituted carboxylic acids and disubstituted ethyl malonates for use as intermediates

ABSTRACT

The present invention relates to substituted tetrahydrofurfuryl aminoesters. The novel tetrahydrofurfuryl dialkyl aminoesters are represented by the formula   in which R is a member of the group formed by the 2-naphthyl, 2naphthyl substituted in the 6-position with alkoxy and 5,6,7,8tetrahydro-1-naphthyl radicals. The addition salts with the therapeutically acceptable acids, the starting and intermediate products of these aminoesters, also form the subject of the invention.

United States Patent Szarvasi DISUBSTITUTED CARBOXYLIC ACIDS AND DISUBSTITUTED ETHYL MALONATES FOR USE AS INTERMEDIATES Etienne Szarvasi, Charbonnieres-les-Bains, France Inventor:

Assignee: Lipha Lyonnaise Industrielle Pharmaceutique, Lyon, France Filed: Sept. 26, 1973 Appl. No.: 400,919

Related US. Application Data Division of Ser. No. 275,638, July 27, 1972, Pat. No. 3,872,112.

Foreign Application Priority Data July 29, 1971 France 71.27823 US. Cl. 260/347.3; 260/347.4; 424/285 Int. Cl. C071) 307/ 12 Field of Search 260/3473, 347.5

References Cited FOREIGN PATENTS OR APPLICATIONS 2/1962 France Oct. 28, 1975 Primary Examiner-Harry l. Moatz Attorney, Agent, or FirmBrowdy and Neimark [57] ABSTRACT The present invention relates to substituted tetrahydrofurfuryl aminoesters. The novel tetrahydrofurfuryl dialkyl aminoesters are represented by the formula 2 Claims, No Drawings DISUBSTITUTED CARBOXYLIC ACIDS AND DISUBSTITUTED ETHYL MALONATES FOR USE AS INTERMEDIATES This is a division of application Ser. No. 275,638, filed July 27, 1972, now US. Pat. No. 3,872,112.

The present invention relates to substituted tetrahydrofurfuryl aminoesters, the processes for the preparation thereof and their applications. it is also concerned with obtaining initial products and intermediate products in the synthesis of these novel aminoesters.

A certain number of aminoesters derived from 3-(1- naphthyl) Z-(Z-tetrahydrofurfuryl)-propionic acid are known which are endowed with vasodilatory and antispasmodic properties, particularly in the U5. Pat. No. 3.445.574 patented on the Mar. 20, 1969 and US. Pat. No. 3.334.096 patented on the Aug. l, 1967, both in the name of Etienne SZARVASI.

These different dialkylaminoesters and particularly the acid oxalate of 2-diethylaminoethyl-3-( lnaphthyl)-(2-tetrahydrofurfuryl)-propionate, sold under the mark Praxilene, contain a l-naphthyl nucleus in their molecule.

It has been found in accordance with the present inin which R is a member of the group formed by the 2- naphthyl radical, the 2-naphthyl radical substituted with alkoxy such as methoxy in the 6-position and 5,6,7,8-tetrahydro-l-naphthyl radical.

It has been discovered that the substitution in the 6- position of the naphthalene nucleus by an alkoxy radical, particularly a methoxy radical, has a favorable influence on the therapeutic activity, while a substitution in the 4-position can correspond to compounds which can be considered as practically inactive, such as the case of 2N-diethylaminoethyl-3-( 4-chlorol naphthyl)-2-( 2 -tetrahydrofurfuryl )-propionate.

The derivatives of these compounds, which also form the subject of the invention, are their addition salts with the acids acceptable for therapeutic uses.

The novel compounds can be obtained according to the invention by condensation of a carboxylic acid of formula:

CH1. I

in which R has the same meaning as previously, with an amino derivative of formula:

in which Y is a halogen, in the presence of an alkali agent. According to one method of procedure, the condensation is carried out under heat in the presence of an alkaline mineral agent, such as potassium carbonate, in an alcoholic solvent medium, such as isopropanol.

For preparing the acid oxalates of the compounds of formula I, the aminoesters as previously obtained are salified with oxalic acid in acetone medium.

The disubstituted carboxylic represented by the formula II, in which R is the possibly alkoxy substituted Z-naphthyl radical, are obtained by saponification and decarboxylation by an alkali in the presence of an alcohol, preferably benzyl alcohol, alkyl malonates of formula:

R-CH,\ cooR.

C CH/ cook,

(III) C H: z s U in which R has the same meaning as previously, which are capable of being used particularly as intermediate products in the preparation of the aminoesters of formula l, are novel and for this reason form part of the invention. v

A process of preparation has also been found, with which it is possible to obtain l-chloromethyl-5,6,7,8- tetrahydronaphthalene in a pure state, free from its isomer, which is a starting product in the preparation of ethyla- [5,6,7,8-tetrahydro-l-naphthylmethyl]-a-(2- tetrahydrofurfuryl)-malonate.

The l-chloromethyl-5,6,7,8-tetrahydronaphthalene in pure form and as such a new industrial product is obtained by reacting (5,6,7,8-tetrahydro-lnaphthyl)methanol with thionyl chloride in the presence of pyridine and in a chlorinated organic solvent medium. The product, obtained by distillation with a purity of 86 is recrystallized in hexane, yielding the chlorinated derivative with a purity of by vapour phase chromatography.

Examples illustrating the invention in non-limiting manner are given below:

I solved in the boilingmixtu' re of 1.00, ml-of'hexane 30 EXAMPLE 1 ml ofethyl acetate.J-After cooling; there are obtained in Ethyl-a-(2-naphthylmethyl)-(2-tetrahydrofurfuryl)- two lots: 25.6 g of white'g crystals, of melting point F malonate 8590C with a yield of'6l (theoretical yield: 42 g).

KJ Cm CO C H I O "Acidity Calculated. i 197 Index f c0432"; Found v l93 I The product is used as such in the sequence of operations, but forthe analytical specimen, it is purified by changing to its methyl ester C I-b 0 M.w. 298.37,

prepared as follows: the following are heated under reflux for 6 hours: 31 g (mol/9.l5) of the above acid in 140 ml of methanol and 7 ml of concentrated H 50 The usual treatment yields 2ll9 gof a yellow liquid of boiling point b.p. l75-l78C with a yield of 67.5 (theoretical yield: 32.5 g). VPC XE 60 (T 260): single peak infrared spectrum conforms. The above ester, when saponified, yields the corresponding acid. For this purpose, there are heated under reflux for 5 hours: 21.3 g (mol/l3.9) of the aboveester, 50 ml of ethyl alcohol and 5 g (4.2 6 g m0l/ 13.1 of 85 KOH. After evaporating the alcohol, the oily, crude potassium salt is dissolved in water. The aqueous solution is washed with ether. Acidification is carried out with hydrochloric acid. An oily precipitate is obtained, which becomes solid and crystalline, when it is taken up in ether. After filtering with suction and washing C l-[ 0 M.w. 384.45

4.5 g (mol/l2) of sodium methylate and 50 ml of ethyl carbonate are placed in a reactor. l9.5 g (mol/l2.5) of ethyl-(2-tetrahydrofurfuryl)-malonate are added thereto. A gentle exothermal reaction is produced, with development of a yellow colouring. Heating under reflux takes place for 30 minutes and the solution becomes brown. After cooling, 15 g (mol/l 1.7) of 2-chloromethyl naphthalene are introduced dropwise. Heating under reflux takes place for 8 hours; with the commencement of the heating, the formation of sodium chloride is confirmed. After cooling, water is added, the organic layer is poured off and dried over anhydrous sodium sulphate.

Distillation of the organic layer permits 18.2 g of a viscous yellow liquid to be isolated, the said liquid hav- I ing a boiling Point 2 0 with a m f 55 with diisopropyl ether, there is obtained a first lot of 5.9 (theoretical yield 323 g) a g of white product with a melting point of 97-99C and vapour phase chromatography (XE 6Q T 2 5 a second lot of 7.3 g of white product, m.p. =6065C. Sing|e peak The yield is 13.2 g, i.e. 64.5 (theoretical yield: 20.5

The first lot, after recrystallisation from hexane and diisopropyl ether (1:1) melts at l04-l05C. White Gravimetl'ic analysis C H 40 crystals.

A.l. Calculated 197 Calculated 71.83 7.33 F d 196 l.R.: co at 1740 cm 1 The lnfrared spectrum obtained can be superlmposed Gravimemc analysis on the spectrum of its l-naphthyl isomer. C% H EXAMPLE 2 Calculated 75.04 a 7.09 Found 76.00 7.07 3-(2-Naphthyl )-2-(Z-tetrahydrofurfuryl)-propionic acid The acid seems to exist in two forms: three and crythro. The second lot probably represents a mixture. The first lot alone was prepared for the analysis. Potassium salt: m'.p. =238240C. -CH--CHCOH EXAMPLE 3 z-U Ethyl-2-diethylarnino-3-(2-naphthyl)-2 (2- tetrahydrofurfuryl) propionate I l l C H O M.w. 284.35

57 g (mol/6.75) of ethyl-a-(2-naphthylmethyl)-a-(2- tetrahydrofurfuryl)-malonate', 20 g of'85 KOH (l7 C,H, g (mol/3.3) are heated under reflux for 8 hours in CH? I 300 ml of benzyl alcohol. The benzyl alcohol is driven off under vacuum. The crude potassium salt is dissolved in water. The aqueous solution is washed with benzene and acidified. An oil precipatates. It is dis- C H NO M.w. 383.51

14.6 g (mol/9.45) of potassium carbonate are placed in 130 ml of isopropanol and there are added there to g (mol/l 1.45) of 2- chlorethyl diethylamine hydrochloride, followed by the solution of 25 g (mol/ll.38) of 3-(2-naphthyl-(Z-tetrahydrofurfuryl)propionic acid in 40 ml of tepid isopropanol. Heating under reflux takes place for 8 hours. After evaporation to dryness,

Gravimetric analysis C H N Calculated 75.18 8.67 3.65 Found 75.20 8.65 3.68

1740 cm CO ester 1600 cm aromatic vibration 3050 benzenic .CH

Acid oxalate C H NO M.w. 473.55.

11.3 g (mol/34) of the above base are dissolved in 15 ml of acetone. This solution is introduced dropwise into a solution of 3.7 g (mol/34) of twice-hydrated oxalic acid in 22 ml of acetone. 10 g of white crystals are obtained, m.p. '7085C. After recrystallisation (ethyl acetate), the yield is 8.8 g 63.5 (theoretical yield: 13.9 g). M.p. 6870C. Following a fresh recrystallisation (ethyl acetate), the product becomes deliquescent on filtering with suction and it is solidified after one 'night in air. White crystals. M.p. 8082C.

A.I Calculated 236 Found 234 'The mother liquors, to which ether is added, yield a second lot, of which the melting point is 9092C.

Gravimetric analysis C H N Calculated 65.95 7.45 2.95 Found 65.9l 7.47 3.00

The infrared spectrum of the first lot can be practically superimposed on its isomer, l-naphthyl, known under the commercial mark of Praxilene.

EXAMPLE 4 l-Chloromethyl-5,6,7,8-tetrahydronaphthalene CH Cl C I-1 C] M.w. 180.66

61 g (0.376 mol) of (5,6,7,8-tetrahydro-lnaphthyl)methanol with a purity of 78 are dissolved in 450 ml of chloroform, in the presence of 35 g (0.38 mol) of pyridine. ml of thionyl chloride in solution in 30 ml of chloroform are introduced dropwise and between 30 and 40C into the solution which is obtained ans this is heated under reflux for 6 hours. After partial evaporation of the chloroform and the thionyl chloride excess, washing is carried out with water and with a sodium bicarbonate solution, followed by drying over anhydrous sodium sulphate. Distillation of the oily residue permits the isolation of a liquid of boiling point b.p. 8l-83C, with a purity of 86 (vapour phase chromatography), and this is taken up in 150 ml of hot hexane. The crystallisation is seeded by scratching with a glass rod. There are isolated 29.5 g ofa product melting at 5152C, with a yield of 56 (theoretical yield 53 g, depending on the degree of purity of the starting product). Vapour phase chromatography confirms a purity of Gravimetric analysis Nuclear magnetic resonance Carbon tetrachloride solvent Internal reference tetramethylsilane 3 aromatic protons at 6. 9-7. lppm 2 benzyl protons at 4.5 ppm 2 groups of4 protons, each at 1.7-2 ppm CH of the tetraline 2.6-3 ppm Total 13 protons.

EXAMPLE 5 Ethyl -a-[5,6,7,8tetrahydro-l-naphthylmethyl1-a-(2- tetrahydrofurfuryl)-malonate Q cH,\c/co,c,in Cl-l/ copni,

C H O M.w. 388.49

- identical and pure at 100 The analytical sample,

twice distilled, has a boiling point b.p. l83-184C. Yield 62 g 70 (theoretical yield 88.5 g).

Gravimetric analysis Calculated 71.1 I 8.30 Found 7l.l5 8.33

Infrared: CO at I740 cm EXAMPLE 6 3-( 5 ,6,7 ,S-tetrahydrol -naphthyl )-2-( Z-tetrahydrofurfury] )-propionic acid C, H .,O M.w. 288.37 62 g (0.1 mol) of ethyloz-(5,6,7,8-tetrahydro-lnaphthylmethyl)-a-(Z-tetrahydrofurfuryl) malonate, 22 g (0.39 mol of 85 KOH and 320 m1 of benzyl alcohol are heated under reflux for 8 hours. The solution is evaporated to dryness under vacuum and the semi-solid residue is dissolved in the minimum quantity of water (200 ml) and the aqueous layer is washed with hexane. After drying the solution and evaporation to dryness, there are obtained 27 g of distillable oil, b.p. 205-207C.

A.I. Calculated 194 Found 184 Infrared, CO badly resolved at 1710 and 1740 cm Yield=27 g=58.5% (theoretical yield 46 g).

The distillate, left for a few days at ambient temperature, starts to crystallise. 50 m1 of hexane and 10 ml of ethyl acetate are added thereto. White crystals are separated out, m.p. 8890C.

After recrystallisation (ethyl acetate-hexane), the constants are as follows:

A.I. Calculated 194 Found 188 Infrared CO at 1700 cm" Gravimetric analysis Calculated 74.96 8.38 Found 74.98 8.35

Subsequently, the crude acid, not crystallised, is used as such. It is also possible to obtain the crystalline form of the acid from the crude, undistilled oil, by adding a mixture of hexane and ethyl acetate.

EXAMPLE 7 N-2-diethylaminoethyl-3-(5 ,6,7,8-tetrahydrol naphthyl)-2-( 2-tetrahydrofurfuryl)-propionate CH,i 1

C H NO M.w. 387.54

8.1 g (0.058 mol) of potassium carbonate are suspended in 135 m1 of isopropanol and there are added thereto 13 g (0.096 mol) of N-diethylamino-Z- chlorethane and a solution of 27 g (0.094 mol) of crude acid from the preceding example, in solution in 45 ml of hot isopropanol. The mixture is heated under reflux for 9 hours. It is evaporated to dryness and the residue is treated with acidified water. It is washed with ether, treated again in basic medium and extracted with ether. Distillation 20 g of light yellow oil, b.p. 193-l C. Yield 20 g 55 (Theoritical yield 36.4 g). Vapour phase chromatography: purity however, the analytical sample is twice distilled, b.p. l75-177C.

Gravimetric analysis C E N Calculated 74.39 9.62 3.61 Found 74.36 9.58 3.63

alic acid in 10 ml of acetone. A few drops of ether are added until cloudiness is formed. it is left in the refrig- Gmvimwic analysis erator and then suction-filtered. 8.8 g of a white prod- C H uct, m.p. 82-84C, are separated with a yield of 93 calcumed 6955 719 (theoretical yield 9.5 g). When recrystallised once Found 69.58 7.30 in a mixture of diisopropyl ether and acetone, the melt- Infrared spectrum ing point remains unchanged. CO 1730 and 1740 A.l. Calculated 234 Found 234 EXAMPLE 9 Gravimwic analysis 3-(6-Methoxy-2-naphthyl)-2-( 2-tetrahydrofurfuryl C H N propionic acid Calculated 65.39 8.23 2.93 Found 65.35 8.23 3.00 Infrared wide band at 3600 to 3400 cm OH 1700 to 17-20 cm" C0.

EXAMPLE 8 20 c14 0 Ethyl-a-[ 6-methoxy-2-naphthylmethyl ]-a-[2- tetrahydrofurfuryl]malonate C I-1 0 M.w. 314.37 5 13.2 g (0.2 mol) of 85 potash, 200 ml of benzyl al- /O==H5 cohol and 41.4 g (0.1 mol) of malonate from Example C 1 are heated under reflux for 8 hours. After heating for 45 minutes, a copious deposit of potassium salt is al- I ready formed. The benzyl alcohol is evaporated under vacuum. The remaining potassium salt is dissolved in water. The aqueous solution is washed with benzene F and then with ether. It is acidified with hydrochloric acid. Copious release of carbon dioxide gas. After scratching, the product crystallises. It is purified, by ex- CMHMO6 MM. 41 4A8 tracting it with ether. After drying the organic layer and 11 g (0.22 mol) of sodium methylate are suspended evaporaftio'n to dryness i? X residue is causefi to in 100 ml of ethyl carbonate and 465 g (019 mol) of crystalllse m 100 ml of bo ling d lsopropyl ether. Yield:

ethyl-(Z-tetrahydrofurfuryl)-malonate are introduced 20 (theorencal yield thereinto. The exothermic reaction causes the temper- 100 407 ature to rise to 40C. Following this reaction, heating 40 Recrystallisaflon under reflux takes place for 1 hour and then there are From 2 g of product m 20 ml of hexane and 70 ml of introduced 40 g (0194 mol) of diistzpropyl ether, there are obtained 1.3 g of m.p. chloromethylnaphthalene, in solution in 140 ml of l5 After a soecond recrystallisation melt' ethyl carbonate. Heating under reflux takes place for 1 mg pomt 1 19 0 hour and then there are introduced 40 g (0.194 mol) of 6-methoxy-Z-chloromethy]naphthalene, In solution in 140 ml of ethyl carbonate. Heating under reflux Acidity index takes place for 16 hours and the sodium chloride which ggki 53 forms is dissolved by adding water. The decanted or- Infrared pectrum ganic layer is re-washed with water. After drying and co at 1720 cm".

Gravimetric analysis evaporating the solvent, an oily residue is obtained C H which is taken up in a mixture of 500 ml of water and C I I 21 cu ated 72.60 7.05 125 ml of alcohol. After cooling, the yellow crystals are Found 7256 m8 suction-filtered. Yield: 61.4 g 77.5 (theoretical 55 yield: 79 g). M.p. -61C (softening at 57C).

The product can be used as such. For the analysis, it is recrystallised from hexane: M.p. 63-65C (white). EXAMPLE 10 The crude oil can be distilled: b.p. 1.2 to 1.3 millibars N-2-Diethy1aminoethyl-3-(6-methoxy-2-naphthyl)-2 229-23lC. 60 (Z-tetrahydrofurfuryl)-propionate l cm, w CH; I 0

c n uo, M.w. 413.53

18 g (0.0575 mol) of the acid of Example 9 are dissolved in 80 ml of isopropanol, and there are added thereto g (0.036 mol) of dry K CO followed by a so-- lnfrared spectrum CO at 1730 cm. Gravimetric analysis C H N Calculated 72.61 8.53 3.38 Found 72.64 8.56 3.37 Acid oxalate C H NO m.w. 503.5 6.

4.] g (0.01 mol of the above base, in ml of ace-v tone, are added to 1.3 g (0.0l mol) of dihydrated oxalic acid in 10 ml of acetone. After being left in the refrigerator and suctionfiltered, the yield is 5 g quantitative.

M.p. l02-l04C. After recrystallisation (ethyl ace.

tate and hexane), the melting point is l02lO3C.

Acidity index Calculated 223 Found 220 Gravimetric analysis C H N Calculated 64.40 7.40 2.78 Found 64.42 7.38 2.77

Infrared spectrum Can be superimposed on that of the acid oxalate of 2-diethylaminoethyl-3-( l-naphthyl)-2-(tetrahydrofurfuryl)-propionate, marketed under the mark Praxilene.

PHARMACOLOGICAL TESTS The peripheral vasodilatory activity was studied by femoral rotametry on the dog.

The control product is the acid oxalate of 2- diethylaminoethyl-3-(1-naphthyl)-2-tetrahydrofurfuryl-propionate, marketed under the mark Praxilene". The activity coefficient is arbitrarily fixed at 100.

The activity, of the acid oxalate of 2- diethylaminoethyl'3-(2-naphthyl)-2-(2-tetrahydrofurfuryl)-pr'opionate (first lot of Example 3)- is at least equal to that of the Praxilene. The Lethal Dose (per os mouse) is equal to 1040 mg/kg. The activity coefficient of the acid oxalate of LN-diethylaminoethyl of 3-(5,6,7,8-tetrahydro-l-naphthyl)-2-(2- tetrahydrofurfuryl)-propionate infemoral rotametry is equal to 100. The LD (per os mouse) is equal to 1350 mg/kg. The activity of the acid oxalate of 2-N- diethylaminoethyl-3-(6-methoxy-2-naphthyl)-2-(2- tetrahydrofurfuryl)-propionate in femoral rotametry is 96 The LD (per os mouse) is equal to 2000 mg/kg.

The new active principles'present a vasodilatory action at cerebral level. It was proved ,with the dog by measuring the blood flow of two vertebral arteries by means of a Shipley-Wilson ratameter.

The comparison with papaverine administered under the same conditions discloses an activity which is three to four times better with the compounds of the invention and which isn'ot accompanied by hypotension, as in the case of papaverine. I

The daily dose sufficient for obtaining the desired therapeutic result on human beings varies from about to 300 mg/kg. y

[t is easy to administer the cornpounds of the invention: the pharmaceutical doses can be formulated in the usual manner with the aid of conventional excipients and adjuvants in the form of tablets, gelatine capsules, injectable solutions, etc.

What I claim is:

l. Disubstituted carboxylic acid, having the formula:

R-CHy-CH-COOH CH l RCH2- I coocm wherein is 2-naphthyl substituted in the 6-position with methoxy.

UNITED STATES PATENT OFFICE (IERTIFHJATE ()F (JORRECTIUN PATENT N0. 3,915,998 Page 1 of 9 DAT D 1 October 28, 1975 INVENTOR(S) Etienne Szarvasi It rs certrfrod that error appears 1n the z1b0verdent:l:ed patent and that said Letters Patent are hereby corrected as shown below:

In the Abstract, add the following paragraph:

--The novel aminoesters and their salts, endowed with peripheral and cerebral vasodilatory properties, are of parti-- cular interest in human therapeutics.--

Column 1, formula (I), delete the formula and insert the following:

2 5 cn 00 C11 c11 N (1) R CH Formula (II), delete the formula and insert the following:

R CH CH COOH UNI'IIID STATES PAIENT ()FFHIF. CERTIFWATE OF C( ')RRE(I'I[()N PATENT NO. 3,915,998 0 DATED 1 October 28, 1975 Page 2 of 9 |NVFNTOR(5) l Etienne Szarvasi It rs rtertltled that error appears in the :rhnverrtentrtlert patent :mrt that send 1. utters Patent are hereby corrected as shown below,

Q Cole 2, Formula (111), delete the formula and insert the following:

R-CH /COOR o /c\ Formula (1V), delete the formula and insert the following:

R-CH 00062115 6 c L 011 CO0C H Q I Page 3 of 9 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIQN PATENT NO. 3,915,998 e DATED October 28, 1975' |NVENTOR(5) 1 Etienne Szarvasi It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

a Col 3, following line 3, delete the formula and insert the following:

0 H2 /COZC2H5 H2 CO C H Col. 3, following line so, delete the formula and insert the following: 7

(ID-m (2H c0 11 Page 4 of 9 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3,915,998 Q DATED October 28, 1975 lNVENTOR( I Etienne Szarvasi It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

0 Col, 4, following line 58, delete the formula and insert the following:

5 e @011 CH co cn N\ Col. 6, before line 10, delete the formula and insert the following:

lCH Cl L Page 5 of 9 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,915,998 6 DATED ;0ctober 28, 1975 |NVENT0R(5) ;Etienne Szarvasi It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Q Col, 6, following line 52, delete the formula and insert the following:

1-H CO C H .0 2 2 5 a /C\ Page 6 of 9 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,915,993

DATED October 28, 1975 INV ENTOR(S) Etienne Szarvasi It is certified that error appears in the ah0ve-identified patent and that said LettersPatent are hereby corrected as shown below:

Col. 7, following line 33, delete the formula and insert the following:

H CH CO H Col. 8, following line 24, delete the formula and insert the following:

J Page 7 of 9 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3,915,998 DATED October 28, 1975 iN\/ ENTOR(S) I Etienne Szarvasi It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown beiow;

Q Col. 9, following line 22, delete the formula and insert the following:

on 0 C I H c co c r1 e 0 Col. 10, following line 113, delete the formula and insert the following:

H2 cu c0 11 a Page 8 of 9 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,915,993 Q DATED October 28, 1975 |NvE T0 (5) Etienne Szarvasi It is certified mar. error appears; m the above-identified patent and that said Letters Patent are hereby corrected as shown beiew:

. Col. 10, following line 60, delete the formula and insert the following:

2 5 0 CH CH CO CH CH N 2 5 CH I i CH r 2 I O O i Col. 12, after line 33, delete the formula and insert the i following:

R-CH -CH-COOH CH2 I or o r i O i I UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF 'CORRECTIUN PATENT NO. 3,915,998

I October 28, g 9 f 9 |NV.ENTOR(S) Etienne Szarvasi tt certified that error appears in the ab0ve-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 12, after line 45, delete the formula and insert the following:

R CH COOC H E lcn cooc H Signed and Sealed this RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner oj'iarents and Trademarks 

1. DISUBSTITUTED CARBOXYLIC ACID, HAVING THE FORMULA:
 2. Disubstituted ethyl malonate having the formula: 